ABSTRACT
Novel bicyclic[1,2,3]triazoles (4, 7, 11, 15) have been synthesized using a one-pot metal free strategy with high structural diversity as photoprotective agents, and their effect on UVA-induced senescence in human dermal fibroblast cells (FB) and the associated mechanism are delineated. 11d plus UVA can induce a decrease in reactive oxygen species (ROS) production and senescence-associated ß-galactosidase (SA-ß-gal) activity but an increase in adenosine triphosphate (ATP) synthesis and mitochondrial membrane potential (ΔΨmt). The mRNA levels of six senescence-associated genes, matrix metalloproteinase-1 (MMP-1), was decreased, while elastin, procollagen I type I, fibronectin, COL1α1, and tissue inhibitor of metalloproteinase-1 (TIMP-1) were increased. 11d plus UVA also decreased MMP-1 and increased TIMP-1 protein levels. Additionally, the thickness of the murine dorsal skin and epidermis, by UVA, was decreased by topical 11d treatment. Our results indicate that bicyclic[1,2,3]triazoles protect UVA-induced senescence-like characteristics in FB cells, which may provide potential prevention against photoaging.
Subject(s)
Fibroblasts/drug effects , Skin Aging/drug effects , Skin/drug effects , Triazoles/pharmacology , Animals , Cells, Cultured , Collagen Type I/genetics , Collagen Type I/metabolism , Collagen Type I, alpha 1 Chain , Drug Design , Elastin/genetics , Elastin/metabolism , Female , Fibroblasts/metabolism , Fibroblasts/radiation effects , Fibronectins/genetics , Fibronectins/metabolism , Gene Expression/drug effects , Gene Expression/radiation effects , Humans , Immunoblotting , Matrix Metalloproteinase 1/genetics , Matrix Metalloproteinase 1/metabolism , Membrane Potential, Mitochondrial/drug effects , Mice , Mice, Inbred ICR , Models, Chemical , Molecular Structure , Reactive Oxygen Species/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Skin/metabolism , Skin/radiation effects , Skin Aging/radiation effects , Tissue Inhibitor of Metalloproteinase-1/genetics , Tissue Inhibitor of Metalloproteinase-1/metabolism , Triazoles/chemical synthesis , Triazoles/chemistry , Ultraviolet RaysABSTRACT
A series of novel pyrrolo[2,1-c][1,4]benzodiazepine (PBD) hybrids linked with enediyne is described. These compounds were prepared by linking C-8 of DC-81 (1) with an enediyne (10-16) through carbon chain linkers to afford PBD hybrid agents 17-23 in good yields. Most of the hybrids on human cancer cell lines exhibited higher cytotoxicity, and an increase in the sub-G1 population than 1. In a previous article, we have demonstrated that DC-81-indole conjugate agents (3-6) are potent inducers of cell apoptosis in melanoma. In the present article, we investigated whether DC-81-enediyne agents possess more cytotoxicity than 6 on human 293T cells. Our data revealed that treatment of 293T cells with DC-81-enediyne resulted in a significant increase of annexin V binding, caspase-3 degradation, and p53 arrest to identify apoptotic cells than 6. These results suggest that the DC-81-enediyne agents are more efficient in inducing apoptosis than DC-81-indole in 293T cells.
